Cancer cells require a constant supply of energy and structural components to support proliferation. Many cancer cells have been shown to have high rates of de novo lipid synthesis (see, for example, Santos & Schulze FEBS J MiniReview 279(15):2610, Jul. 3, 2012). Recently, several therapeutic development strategies have focused on inhibitors of lipid biosynthesis for treatment of cancer.
Two of the most commonly activated pathways in human cancer are the PI3K-Akt and the Ras pathways. The metabolic effects of the PI3K-Akt pathway have been extensively studied, as, in addition to its role in cancer, this pathway is the primary effector of insulin signaling. Akt activation promotes glucose uptake, glycolytic flux, and lactate excretion, i.e., the Warburg effect. In addition, through downstream activation of mTOR, it increases protein synthesis. Finally, Akt induces lipogenesis through mechanisms including enzyme phosphorylation and transcriptional activation, like mTOR-dependent activation of SREBP.
Fatty acids are a primary component of lipids. Their synthesis requires the generation of cytosolic acetyl-CoA (FIG. 1A). In normoxia, a predominant pathway involves catabolism of glucose to pyruvate, which is converted to mitochondrial acetyl-CoA by pyruvate dehydrogenase. Acetyl-CoA is then exported to the cytosol in the form of citrate, which is cleaved to generate cytosolic acetyl-CoA by ATP-citrate lyase, a direct Akt target. In hypoxia, pyruvate dehydrogenase is inactivated by pyruvate dehydrogenase kinase, and glutamine-driven reductive carboxylation accounts for an increased fraction of citrate and thus acetyl-CoA.
Subsequent steps in the fatty acid synthesis pathway are catalyzed by acetyl-CoA carboxylase and fatty acid synthase, which are SREBP targets, and yield palmitate (C16:0, where 16 refers to the number of carbon atoms in the fatty acid, and zero to the number of double bonds). Palmitate in turn is a substrate for various elongation and desaturation reactions to accommodate a cell's need for a diversity of fatty acids, of which the most abundant is the monounsaturated fatty acid oleate (C18:1). Oleate is produced from palmitate by elongation to stearate (C18:0) followed by desaturation by Δ9 stearoyl-CoA desaturase 1 (SCD1), which requires oxygen as an electron acceptor. A specific ratio of oleate to stearate must be maintained by cells to ensure proper membrane fluidity and thus cell integrity, and a significant imbalance has been shown to induce apoptosis. SCD1 is regulated by the PI3K-Akt-mTOR pathway and has been investigated as a pharmacological target for both obesity and cancer.
Like PI3K-Akt pathway activation, Ras activation induces glucose uptake and lactate excretion. While Ras is known to activate the PI3K-Akt pathway, recent findings suggest that downstream metabolic effects may diverge. For example, Ras reduces mitochondrial respiration. In addition, Ras induces macropinocytosis and autophagy, thereby providing potential alternative sources of metabolic substrates. In further support of a divergent metabolic effect, mouse xenograft experiments revealed a difference in sensitivity to caloric restriction between Ras-driven tumors and tumors with PI3K-Akt activation. In contrast to the pro-lipogenic effect of Akt, the impact of Ras on lipid metabolism has not been investigated. Moreover, the interplay of oxygen availability and oncogene signaling on metabolism, including lipid metabolism, has not been extensively explored.
The foregoing observations provide evidence of the continuing need for compositions and formulations useful in treating Ras-driven cancers.